Process of use in perfluoroalkyation and reactant for making use of this process

ABSTRACT

The subject-matter of the present invention is a process of use in perfluoroalkylation and a reactant for making use of this process. This process is defined in that it comprises a stage in which a material of formula RfH and a base (or a species capable of generating a base) are brought into contact, in a polar and anhydrous medium, with a substrate carrying at least one electrophilic functional group. Application to organic synthesis.

This application is a continuation of Ser. No. 09/077,131 filed on Feb.22, 1999 which is a 371 of PCT/FR96/01854 filed Nov. 22, 1996 now U.S.Pat. No. 6,096,926.

The subject matter of the present invention is a process of use inperfluoroalkylation and a reactant for making use of this process. Theinvention more particularly relates to a reactant and a process forgrafting a substituted difluoromethyl group onto a compound containingat least one electrophilic functional group. It more particularlyrelates to a technique for perfluoroalkylating different compounds byaddition or nucleophilic substitution reactions typically carried outwith organometallic derivatives.

Perfluoroalkylation techniques, or equivalent techniques, generally usederivatives of the perfluoroalkyl iodide type, in the presence of zinc.This technique is thus expensive, while requiring plants for thetreatment of the metal wastes which it is advisable to treat, as zinc isa significant pollutant of water courses.

Other techniques, where the perfluoroalkyl radical does not form astabilized reactive intermediate of the organometallic type, aregenerally difficult to employ because of the very low stability of thefree perfluoro anions in the reaction mixtures. The latter generallyresult in products of the carbene type, which, when they react, havelost one of their substituents.

This is why one of the aims of the present invention is to provide areactant which makes possible perfluoroalkylation according to amechanism of the type involving a carbanion, without resorting toorganometallic derivatives of transition metals, such as zinc.

Attempts have often been made to use perfluorocarboxylic acids as sourceof perfluoroalkyl radicals, more generally of trifluoromethyl radicals,by employing decomposition reactions targeted at removing the carboxylfragment from the said acids with release of carbon dioxide. However,the successes which had been achieved were very mixed and usedparticularly complicated catalytic systems. The perfluoroalkyl radicalsor their equivalents generated by the decomposition of the saidperfluorocarboxylic acids were, in addition, unstable in the reactionmixture and required the use of stabilizing agents.

More recently, Shono, in an article entitled “A NovelTrifluoromethylation of Aldehydes and Ketones Promoted by anElectrogenerated Base” and published in J. Org. Chem., 1991, 56, 2-4,attempted to carry out perfluoromethylation reactions from fluoroformand showed that it was very difficult to obtain positive results in theabsence of the base, composed of the pyrrolidonyl anion in combinationwith a quaternary ammonium cation, this being under the expresscondition that this base was generated by electrolysis.

During this comparative study, taking, as test reaction, thetrifluoromethylation of benzaldehyde according to the so-called Barbiertechnique (which will be given in detail hereinbelow), this writerconcluded that the results obtained from other bases gave zero or pooryields and that the side reactions, and in particular the Cannizzaroreaction (disproportionation of benzaldehyde to benzoic acid and benzylalcohol), predominated [but the procedures relating to the usual bases(potassium tert-butoxide, sodium hydride, and the like) are notdescribed therein].

However, the techniques using the electrogenerated bases described bythis writer require, on the one hand, complex equipment and, on theother hand, a dexterity such that they are problematic to reproduce andextremely difficult to extrapolate to industrial scales. Finally, theuse of quaternary ammonium compounds, which are very hygroscopic,implies great care.

The present invention provides a remedy for the disadvantages of theexisting processes by providing a reactant which is non-toxic to theenvironment and which is capable of resulting in the desired productswith a satisfactory yield. These aims and others which will appearsubsequently are achieved by means of a process which comprises a stagein which a material of formula RfH and a base (or a species capable ofgenerating a strong base in the presence of a compound containing mobilehydrogen, such as, for example, toluene; mention may be made, as exampleof such a species, of alkali metals or even alkaline earth metals) arebrought into contact, in a polar and non-protic or only slightly proticmedium, with a substrate carrying at least one electrophilic functionalgroup, provided that, when the substrate is base-sensitive, the additionof the substrate is not carried out last,

either by carrying out the addition, then optionally continuing thereaction after the addition, so that, on the one hand, at least 90% ofthe addition of the final component is carried out and that, on theother hand, the reaction mixture has been maintained for at least ½ hour(including the duration of the addition) at a temperature at most equalto −20° C., advantageously to −30° C.;

or by meeting at least one of the, preferably both, conditionshereinbelow:

the water content is limited to a value at most equal to 200 ppm (twosignificant figures), advantageously to 100 ppm (two significantfigures), preferably to 50 ppm (one significant figure);

or the amount of base is at most equal to 1.3 times the stoichiometricamount with respect to the substrate with a temperature at most equal to0° C. or else the base is at most equal to 1.1 times the stoichiometricamount with a temperature at most equal to 20° C.

It should be pointed out that the above conditions are favourable evenwhen the substrate is not base-sensitive. However, it can sometimes beadvantageous to carry out reactions by departing somewhat from theoptimum conditions when the economic conditions are it.

(cf. the preferred ranges of anhydrousness).

In the present description, H-Rf is understood to mean radicals offormula:

H-(CX₂)_(p)-EWG  (II)

where the X, which are alike or different, represent a fluorine or aradical of formula C_(nF) _(2n+l) with n an integer at most equal to 5,preferably to 2, or a chlorine;

where p represents an integer at least equal to 1 and at most equal to2;

where EWG represents an electron-withdrawing group, the possiblefunctional groups of which are inert under the reaction conditions,advantageously fluorine or a perfluoro residue of formula C_(nF) _(2n+1)with n an integer at most equal to 8, advantageously to 5;

with the condition that X can only be chlorine once on the same carbon.The case where the carbon carrying the hydrogen atom exhibits two Xother than chlorine is particularly advantageous.

It is also desirable that, among the X and EWG, at least one,advantageously 2, are atoms (of chlorine or of fluorine).

The total carbon number of Rf is advantageously between 1 and 15,preferably between 1 and 10.

In the material RfH of the reactant of the invention, the EWG entitywhich exerts an electron-withdrawing effect on the difluoro carbon atomis preferably chosen from functional groups with a Hammett constantσ_(p) at least equal to 0.1. In addition, it is preferable for theinductive component of σ_(p), σ_(i), to be at least equal to 0.2,advantageously to 0.3. In this respect, reference will be made to thework by March, “Advanced Organic Chemistry”, third edition, John Wileyand Son, pages 242 to 250, and in particular to Table 4 in this section.

More particularly, the electron-withdrawing entity can be chosen fromhalogen atoms, preferably light halogen atoms [in particular chlorineand fluorine]. The corresponding material RfH is, when p is equal to 1,a haloform. EWG can also be advantageously chosen from nitrile,carbonyl-containing, sulphonated and perfluoroalkyl-containing groups.Preferred materials of formula RfH of this type which can be usedcorrespond to the formula R-G-CF₂-H

where G represents a divalent group of formula -Z-G′- in which

the divalent Z represents a single bond, a chalcogen atom, or a divalentresidue -Y(R′)-, where R′ is a hydrocarbon-comprising radical of at mostten atoms, advantageously of at most six atoms, advantageously of atmost two atoms, of carbon and where Y is a semimetallic atom from columnV (nitrogen, phosphorus, and the like);

G′ represents >C=O, >S=O, —SO₂—or —(CF₂)_(n)—with n an integer greaterthan or equal to 1;

and where R represents, without distinction, an organic or inorganicresidue, preferably an organic radical such as aryl or alkyl, includingaralkyl, which is optionally substituted. R can also represent a solidinorganic or organic support, such as a resin;

or else the R-G combination represents a nitrile, ester or amide group(advantageously not carrying hydrogen), including a sulphamide group.

In the case where G represents a perfluoro-alkylene group - (CF₂)_(n)- ,n is advantageously between-1 and 10, preferably between 1 and 5.However, in this case, R can also represent a halogen atom, inparticular fluorine.

Thus, according to an advantageous alternative form of the presentinvention, the said material of formula RfH corresponds to the formulaII where EWG represents an electron-withdrawing group of formula III:

R-C_(n)X′_(2n)-   (III)

where n is an integer at most equal to 5, where R is chosen fromhydrogen, a hydrocarbon-comprising radical, such as aryls and alkylscontaining 1 to 10 carbon atoms, and light halogens (chlorine orfluorine, advantageously fluorine);

where the X′, which are alike or different, represent a light halogen(chlorine or fluorine, advantageously fluorine) or a radical of formulaC_(mF) _(2m+1) with m an integer at most equal to 5, preferably to 2.

When R represents a hydrogen, the reaction is more complex, it beingpossible for the said material to react by several ends; and the ratiosof the reactants to one another must take into account this reactivityin the stoichiometry. This polyvalency of the materials can be adisadvantage and, for this reason, the value hydrogen for R is notgenerally desirable.

It is desirable for at least three quarters, advantageously at leastnine tenths, preferably all, optionally less one, of the X and of the X′to be fluorines or perfluoroalkyls (stricto sensu, to be of generalformula of type C_(v)F_(2v+1)).

The acid associated with the said base advantageously has a pK_(a) atleast equal to 15.

However, in order to obtain good results, it is necessary either for thesaid substrate carrying at least one electrophilic functional group tobe very favourable (aldehyde or ketone not having acidic hydrogen at thealpha position) or for the acid associated with the said base to have apK_(a) at least equal to 20, advantageously to 25, preferably to 30.

In addition, especially when the base is in the low region of the abovevalues, it is desirable for the said base to have an associated acidwhich is volatile under the reaction conditions.

Advantageously, the said polar and anhydrous medium is such that thestrongest acid present in the medium, not taking into account thematerial RfH and the substrate, has a pK_(a) at least equal to 25,advantageously to 30, preferably to 35.

The more aprotic the medium, that is to say the lower its content ofprotons which can be released into the reactant, the lower the risk ofside reaction and the better the yield.

Thus, it is preferable, in the reactant, for the content of labilehydrogen atoms to be at most equal to ⅓, advantageously to ¼, preferablyto 10% (in moles), with respect to the initial content of that of thesaid base or of the said material which is not in excess.

This effect is particularly important when the reaction is carried outat a temperature greater than approximately 240° K. (in the presentdescription, the term “approximately” is employed to emphasize the factthat, when the figure or figures furthest to the right of a number arezeros, these zeros are positional zeros and not significant figures,unless, of course, it is otherwise specified).

The main impurity, carrying labile hydrogen atoms, is generally water,which is capable of releasing up to two hydrogen atoms per molecule.

For this reason, the said polar medium is advantageously anhydrous,including substrate and the material RfH, that is to say that it has amolar amount of water less than a third of the amount of baseintroduced, advantageously than a quarter, preferably than a tenth. Thisrestriction on anhydrousness is not very important for processes wherethe reaction is carried out at temperatures of less than 240° K. (twosignificant figures).

Generally, it is preferable to use reactants and solvents which arecarefully dehydrated, so that the content by weight of water in thereactant is at most equal to 1 per 100, advantageously 1 per 1000,preferably to 1 per 10,000, with respect to the total mass of thereactant.

Moreover, it could be shown that other elements, namely transitionelements having two stable valency states, such as copper, might not bepropitious, indeed could be harmful.

Although this reactant according to the invention does not require acatalyst, such metal elements can be present as impurities introduced inparticular by the solvent.

Thus, it is preferable for the molar content of these elements to beless than 1000, advantageously than 100, preferably than 10, ppm withrespect to the initial content of the said material RfH.

Equally, although the use, with perfluoroalkylation agents, of elementsfrom column VIII of the periodic classification of the elements hasfrequently been recommended, in order to promote certain substrates andto promote certain types of reaction, this has not proved to beparticularly propitious for the reaction targeted above. For thisreason, it is preferable to use reactants not containing metals fromcolumn VIII, in particular metals from the platinum lode, which is thegroup composed of platinum, osmium, iridium, palladium, rhodium andruthenium.

In the present description, reference is made to the supplement to theBulletin de la Societe Chimique de France, Number 1, January 1966, wherea periodic classification of the elements was published.

Thus, it is preferable for the content of metals from the platinum lode,indeed of metals from column VIII, to be less than 100 ppm,advantageously than 10 ppm, preferably 1 ppm. These values apply withrespect to the starting base and are expressed in moles.

More generally and more empirically, it may be indicated that these twocategories of metals, namely transition elements with two valency statesand elements from column VIII, should be present in the reactant at anoverall concentration level at most equal to 1000 ppm on a molar basis,preferably to 10 ppm on a molar basis.

It will be noted that the different metals present at such an overallconcentration level are in an extremely low amount and, in this respect,they play no catalytic role. Their presence does not improve thekinetics of the reaction, indeed is harmful to it when they are presentin an excessively large amount.

The use, in addition to the abovementioned reactant components, ofalkali metal fluoride or of quaternary phosphonium fluoride [indeed ofquaternary ammonium fluoride, if the constraints which this type ofcompound engenders are observed], commonly present in the reactantsystems using fluorinated carboxylates, has not proved to be harmful butit has generally proved to be of little advantage, in particular becauseof the fact that it produces saline effluents which are difficult totreat. For this reason, it is preferable to limit their content, inparticular their initial content. Thus, it is preferable for the contentof fluoride, which is described as ionic, that is to say capable ofbeing ionized in the polarizing medium of the reactant, to be at mostequal to the initial molar concentration of the said material RfH,advantageously to half, preferably to a quarter.

The said polar medium can contain solvents.

Even if it is a tautology, it should be recalled that the solvent (whichcan comprise several constituents) must be liquid at the temperatures ofuse.

It may in particular be indicated that it is desirable for the saidsolvent to have a starting freezing point (appearance of a solid phaseresulting from the solvent) at most equal to 10° C., advantageously to0° C., preferably to −10° C. In the case where it is desired to be ableto operate with a greater tolerance of H⁺ and/or of water (a case inparticular where it would be desirable to use quaternary ammoniumcompounds), the choice is advised of a solvent with a starting freezingpoint (appearance of a solid phase resulting from the solvent) at mostequal to −30° C.

Thus, the solvents themselves can be composed of mixtures. Thesemixtures can in particular contain polar solvents and solvents which arenon-polar or only slightly polar, which will be described hereinbelow asdiluent.

As was mentioned above, the solvent plays an important role in thepresent invention and must be aprotic and advantageously polar andcontain very few impurities carrying acidic hydrogen.

It is thus preferable for the polar aprotic solvent which can be used tohave a significant dipolar moment. Thus, its relative dielectricconstant ∈ is advantageously at least equal to approximately 5.Preferably, ∈ is less than or equal to approximately 50 (in the presentdescription, the term “approximately” is employed to emphasize the factthat, when the figure or figures furthest to the right of a number arezeros, these zeros are positional zeros and not significant figures,unless, of course, it is otherwise specified) and greater than or equalto 5.

In addition, it is preferable for the polar solvents of the invention tobe capable of satisfactorily solvating the cations, which can becodified by the donor number D of these solvents. It is thus preferablefor the donor number D of these solvents to be between 10 and 30,advantageously between 20 and 30. The said donor number corresponds tothe ΔH (variation in Enthalpy), expressed in kilocalories, of thecombination of the said polar aprotic solvent with antimonypentachloride. More specifically, the work by Christian Reichardt[Solvents and Solvent Effects in Organic Chemistry, VCH, p.19 (1988)]gives the definition of the donor number, which is defined as thenegative (−ΔH) of the enthalpy (kcal/mol) of the interaction between thesolvent and antimony pentachloride in a dilute dichloromethane solution.

One of the advantages of cryptands is to make it possible to be freed atleast partially from solvents with a high donor number.

According to the present invention, it is preferable for the reactantnot to have acidic hydrogen on the polar solvent or solvents which itcontains. In particular, when the polar nature of the solvent orsolvents is obtained by the presence of electron-withdrawing groups, itis desirable for there not to be hydrogen alpha to theelectron-withdrawing functional group.

More generally, it is preferable for the pK_(a) corresponding to thefirst acidity of the solvent to be at least equal to approximately 20(“approximately” underlining that only the first figure is significant),advantageously at least equal to 25, preferably between 25 and 35.

It is preferable for the base to be at least partially, preferablycompletely, soluble in the medium constituting the reactant. It is thesame with the material of formula RfH.

The polar solvents giving good results can be in particular solvents ofthe amide type. Amides also comprise amides with a specific nature, suchas tetrasubstituted ureas and monosubstituted lactams. The amides arepreferably substituted (disubstituted for ordinary amides). Mention maybe made, for example, of pyrrolidone derivatives, such asN-methylpyrrolidone, or N,N-dimethylformamide or N,N-dimethylacetamide.

Another particularly advantageous category of polar solvents is composedof ethers, whether symmetrical or non-symmetrical, whether open orcyclic. The various derivatives of glycol ethers, such as the variousglymes, for example diglyme, should be incorporated in the category ofethers. Another category may also be cited: sulphoxygenated derivatives,such as sulphoxides and in particular DMSO. Thus, the most appropriatepolar solvents, because of their price and their properties, areadvantageously chosen from ethers, in particular cyclic ethers, such asTHF, or polyfunctional ethers, such as glymes, those of amides which,such as DMF or DAAUs (N,N′-DiAlkylAlkyleneUrea), such as DMEU(N,N′-DiMethylEthyleneUrea) or DMPU (N,N′-DiMethylpropyleneUrea), do nothave acidic hydrogen, and heterocycles with a basic nature, such aspyridine, and their mixtures.

In addition to polar solvents proper, which play a solvation role whichis correlated with the donor number, the solvent can comprise diluentswhich do not have this property. Mention may be made, among diluents, ofaliphatic or aromatic hydrocarbons, such as alkanes or aryl derivatives.Mention should be made of arylmethanes which can both act as diluent(because they are inert under the reaction conditions) and as sources ofbase, when the latter is preprepared in situ.

The countercations capable of potentiating the base, in order to causethe material of formula RfH to react, are advantageously bulky. Thus,alkali metal salts, advantageously those in which the alkali metal ischosen from sodium, potassium, rubidium, cesium and francium, arepreferred. The said metal is preferably from a period with a rank atleast equal to that of sodium, advantageously to that of potassium.Preference is also given to quaternary phosphonium salts, indeedquaternary ammonium salts if the constraints which this type of compoundengenders are observed.

It is also possible to improve the reaction, in particular when thesolvent is ether or contains it, by using cations which are eithernaturally bulky, such as quaternary phosphoniums [indeed quaternaryammoniums, if the constraints which this type of compound engenders areobserved], or rendered bulky by the addition of chelating agents or,preferably, cryptands, such as, for example, crown ethers or derivativeswhich contain both amine groups and oxygen atoms. Although they exhibitthe disadvantage, often prohibitive, of being very hygroscopic,quaternary ammonium cations or cations with a quaternary ammoniumfunctional group can be used, provided that drastic precautions aretaken.

The said substrate can be chosen from halogenated or pseudohalogenatedhydrocarbon-containing compounds, in particular alkyl, aryl or aralkylhalides or pseudohalides, halogenated derivatives of organic siliconcompounds, in particular silane or siloxane halides, halogenatedderivatives of organic sulphur compounds, in particular sulphenyl,sulphinyl or sulphonyl halides, where the halogen atom or thepseudohalogen group is substituted during the reaction by a substituteddifluoromethyl group, or compounds of thiocyanate type where the cyanogroup is substituted during the reaction by a substituted difluoromethylgroup. When the tetrahedral intermediate is present (Grignard techniquein the presence of a carbonyl which can be added to in a stable way:amide) and where the substrate is such that the fluoroalkylationreaction cannot pass (or passes with difficulty) through an additionintermediate, this type of substrate can change, in particular give astable derivative of the tetrahedral intermediate, that is to say thatthe Nucleophilic Substitution takes place via the tetrahedral derivativeand not via the Rf^(−.)

In the above compounds, the halogen atom can be chosen from iodine,bromine, chlorine and fluorine atoms. A “pseudohalogen” group is a groupwhich, starting in the anionic form, has an associated acid with apK_(a) of less than 4, preferably than 3, in particular than 0.

Preference is given to the groups for which the associated acid has anacidity (measured by the Hammett constant) at least equal to that ofacetic acid, advantageously to that of sulphonic acids or ofα-trihalogenated acids. One of the typical pseudohalogens is aperfluoroalkanesulphonyloxy group which releases aperfluoroalkanesulphonate. Preferred pseudohalogen groups can be chosenfrom groups which give a leaving group belonging to the sulphonates, theparadigms of which, because they are the most used, are tosylates(p-toluenesulphonyloxy anion or p-toluenesulphonyloxylate), mesylate(methylsulphonyl-oxylate), triflate (trifluoromethylsulphonyloxylate) orelse α-polyhalogenated carboxylates, one of the paradigms of which istrifluoroacetate. The acyloxylate group (that is to say carboxylate, forexample acetate) can even be regarded as such a leaving group.

During the study which led to the present invention, it was, however,shown that it is desirable for the said substrate to carry at least oneelectrophilic functional group by addition. In other words, for thereaction to take place, at any rate as a transition reaction, byaddition to a functional group exhibiting a double bond (naturallyincluding that of donor-acceptor type) or a doublet belonging to asemimetallic with a period with a rank at least equal to 3.

Thus, according to a particularly advantageous implementation of thepresent invention, such an electrophilic functional group by addition ischosen from carbonyl or thiocarbonyl (>C=S) functional groups,optionally conjugated with one or more bonds of ethylene type,chalcogenides (in which the chalcogen has an atomic rank at least equalto that of sulphur) carrying a good leaving group (see above) and inparticular dichalcogenides (in which the chalcogens have atomic ranks atleast equal to that of sulphur).

Thus, the reactant also advantageously reacts with a compound chosenfrom carbonyl-containing compounds of ketone, aldehyde, activated ester(or acid halide) or non-activated ester type, an addition to thecarbonyl functional group being carried out. The reaction product is analcohol or alkoxide, in which the carbon atom carrying the hydroxylfunctional group is substituted by a substituted difluoromethyl group.These transitory alkoxides, after hydrolysis (generally acidichydrolysis), give the substitution or addition compound. The case ofamides is expanded upon in the passage relating to the tetrahedralintermediate.

When there is a risk of the electrophilic functional group of thesubstrate giving reactions of transesterification type with the base, itis then desirable to choose one or both of the following measures,namely:

that the basicity of the leaving group is similar to or greater thanthat of the base initially employed as reactant,

the route consisting in using the reactant of Grignard type.

In order to avoid certain side reactions, it is desirable for the saidsubstrate not to be acidic or to have a PK_(a) at least equal to 20,advantageously to 25, preferably to 30.

The overall carbon number of the substrate is not limited, other than bythe solubility in the medium (advantageously at least equal to onetenth, preferably one, millimol per litre), and can reach approximately50. However, it is preferable not to exceed approximately 30 carbonatoms.

The reaction is generally carried out at a temperature of between themelting temperature of the medium and the boiling temperature under thepressure conditions of the reaction.

More specifically, the reaction is carried out in the liquid phase, at atemperature of between approximately −100° C. and 160° C.,advantageously between approximately −60° C. and 100° C. When RfH isvery volatile, it is preferable to make sure that there is noevaporation; to do this, it is advisable either to prevent thedifference between the reaction temperature and the boiling point beingexcessively large, more specifically it is desirable to operate at atemperature which is not greater than the boiling point (at atmosphericpressure) by plus 100° C. (two significant figures), advantageously byplus 80° C.; or to operate in a closed vessel, or to operate under ahigh partial pressure of the said RfH or to operate by the Grignardtechnique. It is possible and even advantageous to combine at least twoof the above measures.

Finally, in the case of employing of Barbier type, even under veryanhydrous conditions, the formation of carbene is promoted by thetemperature. This formation of carbene is correlated with the release ofhydrohalic acid, which promotes the side reactions. It is consequentlypreferable to avoid operating at temperatures at most equal to roomtemperature (20° C.) when there is such a risk (essentially when thecarbon number of RfH is equal to 1 or when EWG and/or X is a chlorine).

When the substrate is sensitive to basic degradation, it is alsopreferable to operate at a temperature at most equal to roomtemperature. If there is a twofold risk of formation of carbene andsensitivity to the base of the substrate, it is then preferable not toexceed approximately 10° C. According to an advantageous alternativeform of the present invention, the reaction is carried out so as tointroduce firstly the substrate, then the material RfH and finally thebase. This alternative form will be denoted hereinafter under theexpression of Barbier alternative form [see “March”, fourth edition,page 921 (ref. 365)].

According to particularly advantageous implementation of the presentinvention, the reaction is carried out so as to introduce firstly intothe medium either the material RfH or the base and finally thesubstrate. In other words, to form a reactant from the material RfH,from the base and, if appropriate, from the solvent and/or from thediluent, and then to react this reactant with the substrate. Thisalternative form will be denoted hereinbelow under the expression ofGrignard alternative form.

In the above two alternative forms, the reaction is carried out so as tointroduce the final component of the reactant gradually andadvantageously over a period of time of between 5 and 300 minutes.

The reaction is carried out so as to introduce the said base graduallyand advantageously over a period of time of between 5 and 300 minutes.(cf. description of the reactant below).

In addition, it is desirable, in particular when the reaction is carriedout at “high” temperatures (that is to say, at least equal to 240° K.),for the ratio of the amount of material RfH to the base (RfH/base) to beat least equal to 1, advantageously to 2, times and at most equal to 10;preferably at least equal to 1 three times the stoichiometric amount andat most equal to 5 times.

Especially and mainly if the reaction is being carried out according tothe Barbier technique, when the substrate is sensitive to degradation bybase, it is advisable to restrict the amount thereof and especially theexcess; thus, in the case where the substrates are susceptible todisproportionation, as is the case with aldehydes which can give rise toCannizzaro and/or Tishchenko reactions or crotonization reactions, it isadvisable to limit the amount of base to 4/3, advantageously to 5/4,preferably to 1.1, the S.A. (that is to say, Stoichiometric Amount) withrespect to the substrate.

The use of the so-called Grignard procedure, in particular in thepresence of amide(s) (preferably those targeted as precursor of thetetrahedral compound, cf. below), essentially overcomes the problem andthus makes it possible to use large excesses of base and thus ofreactant. An excess of 20 to 300% is then possible; however, it ispreferable to limit it, for reasons of cost, generally to a value ofapproximately 100%. Of course, the same values are applicable when thesubstrate is sensitive to bases.

Another aim of the present invention is to provide a reactant which canbe used for perfluoroalkylation.

This aim and others which will become apparent subsequently are achievedby means of a reactant containing a material of initial formula RfH anda base (or a species capable of generating a base) in a polar andanhydrous medium.

Advantageously, the reactant additionally contains at least one polaraprotic solvent.

In addition, it is desirable for the ratio of the amount of material RfHto the base (RfH/base) to be between 3 and ½ times the stoichiometricamount.

As has been mentioned above, the solvent plays an important role in thepresent invention and must be aprotic and advantageously polar andcontain very few impurities carrying acidic hydrogen.

It is thus preferable for the polar aprotic solvent which can be used tohave a significant dipolar moment. Thus, its relative dielectricconstant ∈is advantageously at least equal to approximately 5.Preferably, ∈ is less than or equal to 50 (the positional zeros are notregarded as significant figures in the present description unless it isotherwise specified) and greater than or equal to 5.

In addition, it is preferable for the solvents of the invention to becapable of satisfactorily solvating the cations, which can be codifiedby the donor number D of these solvents. It is thus preferable for thedonor number D of these solvents to be between 10 and 30. The said donornumber corresponds to the ΔH (variation in Enthalpy), expressed inkilocalories, of the combination of the said polar aprotic solvent withantimony pentachloride.

According to the present invention, it is preferable for the reactantnot to have acidic hydrogen on the polar solvent or solvents which ituses. In particular, when the polar nature of the solvent or solvents isobtained by the presence of electron-withdrawing groups, it is desirablefor there to be no hydrogen alpha to the electron-withdrawing functionalgroup.

More generally, it is preferable for the pK_(a) corresponding to thefirst acidity of the solvent to be at least equal to approximately 20(“approximately” underlining that only the first figure is significant),advantageously at least equal to 25, preferably between 25 and 35.

It is preferable for the said acid or acid salt and the said material tobe at least partially, preferably completely, soluble in the mediumconstituting the reactant.

The solvents giving good results can be in particular solvents of theamide type. Amides also comprise amides with a specific nature, such astetrasubstituted ureas and monosubstituted lactams. The amides arepreferably substituted (disubstituted for ordinary amides). Mention maybe made, for example, of pyrrolidone derivatives, such asN-methylpyrrolidone, or N,N-dimethylformamide or N,N-dimethylacetamide.

Another particularly advantageous category of solvents is composed ofethers, whether symmetrical or non-symmetrical, whether open or not. Thevarious derivatives of glycol ethers, such as the various glymes, forexample diglyme, should be incorporated in the category of ethers.

Thus, the most appropriate solvents, because of their price and theirproperties, are advantageously chosen from ethers, in particular cyclicethers, such as THF, or polyfunctional ethers, such as glymes, those ofamides which, such as DMF or DAAUs (N,N′-DiAlkylAlkyleneUrea), such asDMEU (N,N′-DiMethylEthyleneUrea) or DMPU (N,N′-DiMethylPropyleneUrea),do not have acidic hydrogen, and heterocycles with a basic nature, suchas pyridine.

When they are employed, the amides used play a greater role than appearsat first glance and they play a role in the formation of the reactant.This is because it has been possible to demonstrate that the reactantformed in the amides (especially when they correspond to the precursorof the formula of the tetrahedral compound hereinbelow) was a reactantin which the reactive species was the addition compound of CF³⁻ to thecarbon of the carbonyl functional group, the oxygen of the latterfunctional group becoming anionic. It is this compound which acts ascarrier of CF³⁻ or more specifically of Rf−. An important characteristicof this novel reactant is consequently the presence of this species inthe reactant. The present invention is consequently also targeted atreactants containing the compounds of formula (IV) Rf-C[O⁻(M⁺)] [R₁₃][N(R₁₁) (R₁₂)]

Of course, the above formula is also targeted at the other enantiomer.This intermediate can be identified by fluorine NMR (in the case ofdimethylformamide, δ of approximately 1 ppm [doublet difficult toresolve] with respect to HCF₃). In this formula, M⁺ represents anadvantageously monovalent cation corresponding to the bases specified inthe present description; advantageously alkali metals and phosphoniums.Rf has already been defined above, and R₁₁, R₁₂ and R₁₃ representhydrocarbon-comprising or aryl chains, including alkylaryl or alkylchains, including aralkyl and cycloalkyl chains, it being possible forthese chains to be connected to one another in order to form one (ormore) ring(s). As regards R₁₃, R₁₃ has a Hammett constant value of lessthan 0.2 in absolute value, preferably than 0.1.

However, R₁₃ can also take the value hydrogen and this is its preferredvalue. Another value satisfying R₁₃ is the value aryl, the Hammettconstant of which is advantageously less than 0.2 in absolute value,preferably than 0.1. This intermediate exhibits good stability, inparticular at low temperatures (for example −10, advantageously −20,preferably −30° C.). Thus the present invention is targeted at areactant of the above type which contains at least one compound offormula IV at a concentration at least equal to one millimol per litre,advantageously to 5 millimol per litre, preferably 10 millimol perlitre.

This intermediate can act as perfluoroalkylation reactant, as describedabove, but can also constitute a reaction intermediate resulting inadvantageous compounds, in particular aldehyde, O-silylated derivative,(bi)sulphite derivative or O-acylated derivative.

When it is used as perfluoroalkylation reactant, it is preferable forthe R₁₁, R₁₂ and R₁₃ groups to be small in size, that is to say for,when they are alkyls, their carbon number to be advantageously at mostequal to 6, advantageously to 3, preferably methyls; when they arearyls, advantageously phenyls (substituted or unsubstituted), it ispreferable for their carbon number advantageously to be at most equal to10, advantageously to 8. It is preferable for the R₁₁, R₁₂ , and R₁₃groups to have, overall, a carbon number at most equal to 15,advantageously to 12, preferably to 8.

When it is not used as perfluoroalkylation reactant but as syntheticintermediate, the R₁₁, R₁₂ and R₁₃ groups can be greater in size(provided that it is soluble in the medium) and the overall carbonnumber can then reach approximately 50. However, it is preferable not toexceed approximately 30 carbon atoms.

It is therefore highly recommendable, on using the Grignard reactant, touse, alone or as a mixture (optionally with other amides), amides offormula R₁₃—CO—N(R₁₁) (R₁₂), the recommended ratio of these amides tothe base used then being at least equal to 1, advantageously to 2,preferably to 5. There is no upper limit, except that it (they)constitute(s) all the polar solvent. When these amides are used assolvents more often than not in the tests carried out (without thisnecessarily being an optimum), the content of these amides with respectto the sum of the polar solvents is between approximately 40 and 80%.

Mention may be made, among the diluents, of aliphatic or aromatichydrocarbons, such as alkanes or aryl derivatives. Mention should bemade of arylmethanes which can both act as diluent (because they areinert under the reaction conditions) and as sources of base when thelatter is preprepared in situ.

The following non-limiting examples illustrate the invention.

TYPICAL PROCEDURE: FLUOROFORM “Barbier” Method

Fluoroform 0 is added by bubbling to a suitably stirred solution* ofsubstrate in the anhydrous solvent at most equal to approximately 100ppm (mass) maintained at −50° C. The bubbling into this solution iscarried out over approximately 15 min. A base, generally in solution ina polar solvent, generally ether [cyclic or non-cyclic, such as THF,symmetrical or non-symmetrical dialkyl ether (for example, dimethylether, diethyl ether, dibutyl ethers, methyl ethyl ether, and the like),or polyether, such as glymes], is then added dropwise over 20 min, thetemperature being maintained at −50° C.

The reaction mixture is left without stirring at −50° C. for anadditional 10 min.

An excess of acetic acid is added at this same temperature and thetemperature is allowed to rise to room temperature. *Handling under aninert argon atmosphere.

“Grignard” Method

A base or a solution of base in a polar solvent, generally ether [cyclicor non-cyclic, such as THF, symmetrical or non-symmetrical dialkyl ether(for example, dimethyl ether, diethyl ether, dibutyl ethers, methylethyl ether, and the like), or polyether, such as glymes], is addeddropwise at −40° C. and over a period of 10 min to a suitably stirredsolution* of fluoroform in anhydrous DMF.

The reaction mixture is left without stirring for 30 min at −40° C.,before adding the substrate.

This solution is kept without stirring at −40° C. for an additional 30min, before the addition of acetic acid.

The temperature is allowed to rise to room temperature and thecomposition of the mixture is determined by GLC assaying with internalcalibration.

EXAMPLE NO. 1 ROLE OF THE ORDER OF ADDITION OF THE REACTANTS GeneralProcedure 1 (so-called “Barbier” method)

Fluoroform (4.9 g, 70 mmol) is added over a period of 15 minutes to asuitably stirred solution (400 r/min), maintained at −50° C., ofbenzaldehyde (0.64 g, 6 mmol) in anhydrous DMF. A 1 M solution of t-BuOKin THF (5 ml, 5 mmol) is then added dropwise over 20 minutes, thetemperature being maintained at −50° C.

The reaction mixture is left stirring at −50° C. for an additional 10minutes, before addition of acetic acid (0.5 ml).

The composition of the mixture is determined by GLC assaying withinternal calibration:

DC(PhCHO)=74%

RY(PhCHOHCF₃)=60%

RY(PhCH₂OH)=0.3%

It is noticed, and this is general throughout the Application, that, inparticular for base-sensitive substrates, an amount of base of less thanstoichiometry with respect to the substrate gives excellent results inthe Barbier method.

General procedure 2 (so-called “Grignard” method)

A 1 M solution of t-BuOK in THF (5 ml, 5 mmol) is added dropwise at −40°C. over a period of 10 minutes to a suitably stirred (400 r/min)solution of fluoroform (3.0 g, 43 mmol) in 30 ml of anhydrous DMF. Thereaction mixture is left stirring for 30 minutes at −40° C., beforeadding benzaldehyde (0.47 g, 4.4 mmol).

The solution is left stirring at −40° C. for an additional 30 minutes,before addition of acetic acid (0.5 ml).

The composition of the mixture is determined by GLC assaying withinternal calibration:

DC(PhCHO)=67%

RY(PhCHOHCF₃)=46%

RY(PhCH₂OH)→traces

EXAMPLE No. 2 ROLE OF THE SIDE REACTIONS (CANNIZZARO REACTION ACCORDINGTO T. SHONO)

In the reaction between benzaldehyde and the CF₃H/t-BuOK/DMF system, ifthe operating conditions are not well chosen, side reactions (and inparticular formation of benzyl alcohol attributed to the Cannizzaroreaction by T. Shono) predominate.

General procedure 1 (variation in the reaction temperature and in thenumber of equivalents of base employed).

Experimental Parameters DC (2) % YD (4) % YD (5) % Excess of base (2.2eq) at −50° C. 97 69 — Excess of base (1.5 eq) in the presence of water98 70 6 (20 mol %/t-BuOK employed) at −50° C. Base (1 eq) at −10° C. 8873 3 Excess of base (1.5 eq) at −10° C. 100 19 —

An excess of base: in the presence of a large excess of base (2.2 eq) at−50° C., the formation of benzyl alcohol does not take place.

The presence of water: if one of the reactants is of poor quality, itcan contain a small amount of water which would induce the Cannizzaroreaction. However, at −50° C., in the presence of water (20 mol %/t-BuOKemployed), scarcely 6% of benzyl alcohol is detected.

The heat level: at −10° C. in the presence of 1 equivalent of base, theformation of benzyl alcohol does not take place; on the other hand, theexcess of base/heat level (−10° C.) combination promotes this reaction,since the trifluoromethylation yield falls from 70 to 19%.

EXAMPLE No. 3 ROLE OF THE NATURE OF THE SOLVENT

Fluoroform (3 g, 42.85 mmol) is added at −10° C. to a suitably stirred(400 r/min) solution of t-BuOK (0.53 g, 4.7 mmol) in 30 ml of anhydroussolvent (S). The reaction mixture is left stirring for 30 minutes at−10° C., before adding benzaldehyde (0.47 g, 4.4 mmol).

The solution is left stirring at −10° C. for an additional 60 minutes,before addition of acetic acid (0.5 ml).

The composition of the mixture is determined by GLC assaying withinternal calibration:

Solvent RY (3) % THF 25 DMF 57 N-Formylpiperidine 5

EXAMPLE No. 4 ROLE OF THE NATURE OF THE BASE Associated cation (Generalprocedure of type 2)

t-BuOM^((a)) θ° C. T (min) DC (3) (%) RY (4) (%) YD (4) (%) RY (5) (%)YD (5) (%) t-BuOK −20 30 88 64 73 traces — t-BuONa −20 30 83 59 71traces — t-BuOLi −20 30 32.5 13 40 traces — ^((a))CF₃H/t-BuOM/PhCOH(9/1.1/1).

Type of base (General procedure of type 1)

Base BH Operating Conditions 1/3/2 θ° C. DC (2) (%) RY (4) (%) RY (5)(%) t-BuOK 9/1.1/1 −15° C. 88 64 3 KH (comparative) 7.8/1.2/1  25° C. 709 11 NaH/DMSO 9/1.3/1  0° C. 94 50 — NaH/DMSO + 15-crown-5 9.3/1.3/1 + 1eq 15-crown-5 −10° C. 96 65 — KH/DMSO 8.7/1.15/1 −15° C. 91 66 3

EXAMPLE No. 5 DEMONSTRATION AND ROLE OF THE TETRAHEDRAL INTERMEDIATE 1.Synthesis of fluoral hemiaminal and of derivatives

Fluoroform (3 g, 42.85 mmol) is added at −10° C. to a suitably stirredsolution of base in 30 ml of anhydrous DMF. This solution is kept at−10° C. for 30 min and then the following are added dropwise at the sametemperature:

AcOH (0.37 g, 6.2 mmol), in the case where R=H (base: KH/DMSO, 5.7mmol),

Me₃SiCl (1.3 ml, 10.25 mmol), in the case where R=Me₃Si (base: KHMDZ, 7.mmol)

SO₂ (0.8 g, 12.5 mmol), in the case where R=SO²⁻ K+(base: KH/DMSO, 5.9mmol).

The reaction mixture is then kept at this same temperature for 30minutes, before allowing it to rise to room temperature.

The products formed were identified by ¹H, ¹⁹F and ¹³C NMR.

RX RY (assayed) AcOH 3a, 76% Me₃SiCl 3b, 79% SO₂ 3c, 77%

2. Synthesis of fluoral hydrate

Fluoroform (3 g, 42.85 mmol) is added to a suitably stirred solution,maintained at −15° C., of t-BuOK (5.mmol) in an anhydrous solvent (30ml). After 30 min at this temperature, the reaction mixture is acidifiedwith 2 ml of sulphuric acid.

The following table gives the results as fluoral hydrate as a functionof the operating parameters:

Solvant RR (3) ⁽¹⁾ % DMF 60

56

52 ⁽¹⁾ ¹⁹F NMR assaying with internal standard.

EXAMPLE No. 6 Synthesis of 2,2,2-trifluoroacetophenone

Fluoroform (3.0 g, 43 mmol) is added at −10° C. to a suitably stirred(400 r/min) solution of KHMDZ (1.15 g, 5.75 mmol) in 30 ml of anhydrousDMF. The reaction mixture is left stirring for 30 minutes at −10° C.,before adding methyl benzoate (0.51 g, 3.75 mmol) dropwise.

The solution is left stirring at −10° C. for an additional 1.5 hours,before addition of acetic acid (0.6 ml).

After a conventional treatment of the reaction mixture (extraction anddistillation), trifluoroacetophenone is isolated with a yield of 55%.

EXAMPLE No. 7 1,1,1,3,3,3-Hexafluoro-2-phenyl-2-propanol

Fluoroform (3.0 g, 43 mmol) is added at −10° C. to a suitably stirred(400 r/min) solution of potassium dimsylate (5.85 mmol) in 30 ml of ananhydrous DMF/DMSO (2/1) mixture. The reaction mixture is left stirringfor 30 minutes at −10° C., before adding trifluoroacetophenone (0.615 g,3.5 mmol) dropwise.

The solution is left stirring at −10° C. for an additional 1 h 10,before addition of acetic acid (0.6 ml).

The composition of the mixture is determined by ¹⁹F NMR and GLC assayingwith internal calibration:

DC(PhCOCF₃)=35%

RY(PhCOH(CF₃)₂)=79%

YD(PhCOH(CF₃)₂)=44%

EXAMPLE No. 8 Synthesis of Aryl Trifluoromethyl Sulphide (ArSCF₃)

Fluoroform (3 g, 42.85 mmol) is added to a suitably stirred solution,maintained at −30° C., of ArSX (X═SAr, SO₂Ph, Cl, 4 mmol) in 30 ml ofanhydrous DMF. A 1M solution of t-BuOK in THF (5 ml) is added dropwiseto this solution and the mixture is maintained at −30° C. for 30 to 40min, before acidification with AcOH. The composition of the mixture isdetermined by ¹⁹F NMR and GLC assaying with internal standard. Theproducts are then isolated after a conventional treatment.

The results obtained are collated in the following table:

DC (1) ⁽¹⁾ RY (2) ⁽²⁾ YD (2) Ar X (%) (%) (%) Ph SPh 56.5 77 136 PhSO₂Ph 100 90 90 4-NO₂Ph Cl 100 22 22 ⁽¹⁾ GLC assaying ⁽²⁾ GLC and ¹⁹FNMR assaying

EXAMPLE No. 9 ROLE OF THE OTHER HALOFORMS General Procedure

Approximately 5 g of potassium tert-butoxide and then 120 ml ofanhydrous DMF are introduced into a completely stirred 500 ml reactorcontaining a mechanical stirrer (650 r/min) which is maintained under anitrogen purge. The reaction mixture is then cooled to −40° C. by meansof an acetone/dry ice bath. Approximately 5 g of benzaldehyde are thenintroduced dropwise, followed by 3 to 4 equivalents of haloform, bybubbling into the reaction mixture if it is gaseous (CCl₂FH, CF₃CF₂H),dropwise if it is liquid (CCl₃H). After stirring for one hour between−40 and −45° C., 5 ml of concentrated acetic acid are added dropwise andthen the reaction mixture is allowed to return to room temperature. Thecrude reaction mixture is analysed by GLC and then by coupled GLC/MS, inorder to identify the product and the by-products formed.

The reaction mixture is diluted in 150 ml of water and then the productsare extracted with ethyl acetate (3×170 ml). The combined organic phasesare then washed 4 to 6 times with 100 ml of water, in order to removethe DMF (GLC monitoring), and then twice with 50 ml of saturated NaClsolution. The organic phase is then dried over anhydrous MgSO₄ for 30 to60 minutes and then filtered on sintered glass.

If the boiling temperature of the compound synthesized is sufficientlyhigh, the ethyl acetate can be evaporated on a rotary evaporator under avacuum of 20 mm Hg and at a temperature of 35° C.; in the contrary case,ethyl acetate is then distilled off at atmospheric pressure.

Fractional distillation is carried out under a vacuum of approximately15 mm Hg. The carbinol is thus isolated with a purity of greater than90%.

CXYZH Boiling point^((b)) (1) ^((a)) (2) ^((a)) (3) ^((a)) DC (1) (%) RY(4) (%) CF₃H −80° C. 1 1 8.6 94 67 CF₃CF₂H −50° C. 1 1 4 98.5 71 CCl₂FH 10° C. 1 1 3 −100 64 ^((a)) - Number of equivalents ^((b))- Rounded offand at atmospheric pressure

What is claimed is:
 1. A perfluoroalkylation process, comprising thesteps of: reacting a compound of formula RfH, wherein Rf is aperfluoroalkyl group, and a base or a species capable of generating abase, in a polar medium, with a substrate, having a pK_(a) at leastequal to 20, added to said polar medium and carrying at least oneelectrophilic functional group, selected from the group consisting ofcarbonyl, thiocarbonyl(>C=S) optionally conjugated with one or morebonds of ethylene type and a chalcogenide carrying a leaving group, thencarrying out the addition, then optionally continuing the reaction afterthe addition, so that, on the one hand, at least 90% of the addition ofthe product of formula RfH, the base, or the substrate to the polarmedium to form a reaction mixture is carried out and that, on the otherhand, said reaction mixture has been maintained for at least ½ hour,including during the addition, at a temperature at most equal to −20°C.; or meeting at least one of the conditions herein below: limiting thewater content to a value at most equal to 200 ppm; or maintaining anamount of base at most equal to 1.3 times the stoichiometric amount ofsaid base with respect to the substrate with a temperature at most equalto 0° C., or else the base is at most equal to 1.1 times thestoichiometric amount of said base with a temperature at most equal to20° C.
 2. A process according to claim 1, wherein the water content isat most 50 ppm.
 3. A process according to claim 1, wherein said compoundof formula RfH corresponds to the following formula: H−(CX₂)_(p)−EWGwherein: the X, which are alike or different, represent a chlorine, afluorine or a radical of formula C_(n)F_(2n+1) with n being an integerat most equal to 5, p represent an integer at most equal to 2, and EWGrepresents an electron-withdrawing group, inert under the reactionconditions.
 4. A process according to claim 3, wherein EWG is a fluorineor a perfluoro residue of formula C_(n)F_(2n+1) with n being an integerat most equal to
 8. 5. A process according to claim 4, wherein said EWGis a group of formula III: R−C_(n)X′_(2n)−  (III) wherein: n is aninteger at most equal to 5, R is hydrogen, an alkyl group containing 1to 10 carbon atoms, chlorine, or fluorine, and the X′, which are alikeor different, are chlorine, fluorine, or a radical of formulaC_(m)F_(2m+1) with m an integer at most equal to
 5. 6. A processaccording to claim 1, wherein said base has an associated acid, thepK_(a) of which is at least equal to
 15. 7. A process according to claim6, wherein the associated acid is volatile under the reactionconditions.
 8. A process according to claim 1, wherein said polar mediumis such that the strongest acid present in the medium, the compound RfHand the substrate being excluded, has a pk_(a) at least equal to
 25. 9.A process according to claim 1, wherein said polar medium, including thesubstrate and the compound product RfH, exhibits a molar amount of waterof less than a quarter of the amount of base added.
 10. A processaccording to claim 1, wherein said polar medium is anhydrous, includingthe substrate and the compound RfH, and exhibits a molar content ofwater at most equal to a third of the amount of base added.
 11. Aprocess according to claim 10, wherein said polar and anhydrous mediumcontains at least one solvent with a donor number at least equatl toapproximately
 10. 12. A process according to claim 10, wherein saidpolar and anhydrous medium contains at least one solvent with a relativedielectric constant ∈ at least equal to
 5. 13. A process according toclaim 1, wherein the reaction is carried out at a temperature of betweenthe melting temperature and the boiling temperature of the medium underthe pressure conditions of the reaction.
 14. A process according toclaim 1, wherein the reaction is carried out at a temperature of between−50° C. and 160° C.
 15. A process according to claim 1, furthercomprising the steps of adding firstly to the medium the substrate, thenthe material RfH and finally the base to the polar medium.
 16. A processaccording to claim 1, furhter comprising the steps of adding firstly tothe medium of material RfH, or the base and finally the substrate.
 17. Aprocess according to claim 1, wherein the compound of formula RfH, thebase, or the substrate is added gradually to the polar medium. over aperiod of time of between 5 and 300 minutes.
 18. A process according toclaim 17, wherein the compound of formula RfH, the base, or thesubstrate is added to the polar medium. over a period of time of between5 and 300 minutes.
 19. A process according to claim 1, wherein thecompound of formula RfH, the base, or the substrate are added to thepolar medium in such an amount that the ratio of the amount of materialRfH to the base is at least equal to 1.5 times the stoichiometricamount.